Entering the army in 1884 as a second lieutenant, De Bono rose to a place on the general staff in the Italo-Turkish War (1911). In World War I he distinguished himself against the Austrians at Gorizia (1916) and Grappa (October 1918). He was discharged with the rank of major general in 1920.

He helped organize the Fascist party, and in 1922 he participated with Mussolini in the famous March on Rome, which signaled the beginning of the Fascist regime. After serving as chief of police and commander of the Fascist militia, he was appointed governor of Tripolitania. Named commander in chief when Italy invaded Ethiopia in 1935, he was quickly replaced by the more talented General Pietro Badoglio, though he was rewarded with the rank of field marshal.

Appointed minister of state in 1942, De Bono participated in the historic meeting of the Fascist Grand Council (July 24/25, 1943) and was among those who voted against Mussolini, thus causing the leader's downfall. When Mussolini regained power in northern Italy with German help, he had De Bono arrested, tried for treason, and executed by a firing squad.